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Molecular Mechanisms of Intestinal Atrophy/Hyperplasia

肠萎缩/增生的分子机制

基本信息

批准号：
8017413
负责人：
RICHARD A. HODIN
金额：
$ 34.15万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8017413
关键词：
Acetylation Affect Alkaline Phosphatase Antibodies Atrophic Award Binding Biological Assay Biological Models Cell Culture System Cell Culture Techniques Cell physiology Cells Chromatin Chromatin Structure Clinical Dietary Fats Differentiation Antigens Disease Dissection Enterocytes Epithelial Epithelial Cells Failure Functional disorder Funding Gene Activation Gene Expression Gene Expression Regulation Gene Silencing Gene Targeting Genes Genetic Transcription Histone Code Histones Hyperplasia In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Intestines Lead Lipopolysaccharides Methylation Microbe Modification Molecular Morbidity - disease rate Nucleic Acid Regulatory Sequences Pathologic Pathway interactions Patients Phenotype Physiological Physiology Play Precipitation Process Proteins Research Design Research Personnel Research Proposals Resistance Role Salmonella Sepsis Serum Starvation Stress Toxin Transcriptional Activation Trauma Work absorption base chromatin immunoprecipitation cytokine deprivation gastrointestinal epithelium gene repression genetic regulatory protein in vitro Model in vivo in vivo Model mortality programs response therapeutic target transcription factor

项目摘要

We have identified an important adaptive response that occurs in the mammalian gut in the setting of starvation and disease, silencing of the enterocyte differentiation marker gene, intestinal alkaline phosphatase (IAP). Based upon its functions in regard to dietary fat absorption and cellular resistance to toxins (such as LPS) and microbes, the silencing of IAP expression likely has important physiological consequences for the host. As such, the broad aims of this proposal are to delineate the mechanisms that govern IAP gene regulation. Ultimately, we hope to identify therapeutic targets that could be used in the clinical setting to treat patients in the context of starvation and other gut-related conditions. The three specific aims of this proposal represent complementary and distinct approaches to understanding enterocyte differentiation in both normal and pathologic conditions. Aim#1 is based upon our observation that ectopically expressed IAP leads to a remarkable change in enterocyte phenotype, characterized by resistance to LPS and Salmonella. Accordingly, we will examine three transcription factor pathways that activate IAP expression (KLF4, Cdx1, and ZBP-89). Each of these factors will be expressed within intestinal epithelial cells in vitro in order to determine whether they result in altered host cell function in regard to LPS and Salmonella. In Aim #2 we will dissect a single transcriptional pathway using a well-established inducible cell culture system. Chromatin Immuno-precipitation (ChIP) will be used to define the precise changes in chromatin structure that occur when an individual transcription factor (KLF4) binds and activates a specific target gene (IAP). We will examine the secondary modifications that occur in the histone proteins in response to KLF4 binding, the role of associated proteins, and also determine those changes that occur as the IAP gene is turned off. In Aim #3 we will focus on the enterocyte adaptation that occurs in response to diseases and stress. We will use both in vitro and in vivo model systems to examine the molecular mechanisms that govern IAP gene repression in the contexts of starvation and inflammation. Taken together, these studies will have important implications for our understanding of normal intestinal physiology, as well as the gut response to disease states.

我们已经确定了一种重要的适应性反应，发生在哺乳动物的肠道